Vocal fold paralysis occurs when the recurrent laryngeal nerve (RLN) is injured, most commonly during surgery of the neck or thorax. Immobility of one vocal fold produces a hoarse voice, reduced airflow and aspiration of fluids with swallowing that can lead to pneumonia. Bilateral injury to the RLN can result in potentially life- threatening airway obstruction and the need for tracheostomy. The RLN can regenerate some of its axons, but more than half of patients with paralysis require some form of intervention to correct the airway obstruction and voice changes. This is mostly frequently achieved through reinnervation of the laryngeal muscles to restore function. As spontaneous recovery can occur, current practice is to wait 6-12 months before any intervention is performed. This delay produces chronic changes in the nerve distal to the site of injury and reduces the capacity of axons to regrow and reinnervate the muscles controlling the vocal folds. Our preliminary data definitively demonstrate that the type of macrophages infiltrating the site of nerve repair have a significant impact on healing when reinnervation is delayed. We hypothesize that promotion of an alternately activated or regulatory macrophage phenotype at the site of nerve repair promotes axonal regrowth and functional recovery. In specific aim 1, we will use transgenic knock-out mice to demonstrate the effects of deletion of cell surface receptors that control macrophage phenotype on nerve repair immediately and up to 4 months after injury. We will use mice with deletions for receptors for IFN, IL4 and IL10 which, if present, promote classical, alternate or regulatory responses. We will establish the effects of nerve repair immediately and up to 4 months after nerve injury using retrograde labeling. In the second aim, we will use a hydrogel system to deliver high and low dose IL4 and IL10 for a prolonged period to the site of nerve repair in an established model of chronic nerve injury. Nerve repair will be performed at 2 months after injury and axonal regrowth and functional recovery assessed for 4 months after repair. These experiments will improve the understanding of immunomodulation in nerve repair and have their greatest application for RLN injuries or potentially in laryngeal transplantation. T achieve these goals, I have built an exceptional interdisciplinary team who are leading experts in their respective fields to provide support and guidance in clinical translation, immunology, peripheral nerve repair, macrophage phenotype in remodeling and host response. This team will support me in this proposal and through my transition to independence.